Published on October 15, 2007
THE McCUNE ALBRIGHT SYNDROME: THE McCUNE ALBRIGHT SYNDROME and THE HISTORY OF THE G-PROTEIN Alan Davidson THE PATIENT: a 3 year old boy: THE PATIENT: a 3 year old boy 3 week history of ... painful left leg associated limp NO systemic symptoms Background: 2kg normal vertex delivery with good Apgars Normal milestones Findings on Examination: Findings on Examination NOT frankly dysmorphic Wt 25th centile Ht 50th centile Pale NO nodes, liver or spleen NO swelling or tenderness of the left hip with full range of motion. However … Slide4: There was subtle bossing of the skull ... Slide5: … and extensive hyperpigmentation on the trunk and limbs. This consisted of multiple macular lesions with irregular margins. Several showed distinct cutoff at the midline. He was referred to Orthopaedics who arranged a plain Xray of his hip and a bone scan ...: He was referred to Orthopaedics who arranged a plain Xray of his hip and a bone scan ... XRAY Left Hip Bone Scan: XRAY Left Hip Bone Scan What do you see? XRAY Left Hip and Bone Scan: XRAY Left Hip Irregular lytic and sclerotic areas in proximal femoral metaphysis and neck Bone Scan Widespread patchy uptake in all bones Intense uptake in maxilla and base of skull Fearing a systemic malignancy such as Leukemia or Neuroblastoma, the Orthopaedic Service referred him to the Oncology Service for assessment. XRAY Left Hip and Bone Scan Radiology: Radiology X-Rays showed ground glass sclerosis of the base of skull and orbital margins. Skeletal survey showed multiple non-homogeneous foci of lysis and sclerosis in the vertebrae and long bones. Laboratory Results: Laboratory Results FBC: Hb 8.1 MCV 50 Plt 426 WCC 10 ESR 17 Chemistry: Urea 3.2 Creat 34 LDH 195 ALP 598 Iron Studies: Fe: 0.9 TIBC 102 Sats 0.9 Ferritin: < 15 Thyroid functions: T4: 33.3 TSH: 0.03 PTH / FSH / LH: Normal levels How do you interpret these results? Laboratory Results: Microcytic Anaemia … probably iron deficiency ... confirmed by iron study results Normal ESR Normal LDH … predicates against leukemia / lymphoma Raised ALP … result of increased bone turnover Raised T4 and low TSH indicate primary hyperthyroidism How can we put this all together ? Laboratory Results THE BIG PICTURE ?: THE BIG PICTURE ? Bony changes which are typical of POLYOSTOTIC FIBROUS DYSPLASIA CUTANEOUS HYPERPIGMENTATION HYPERTHYROIDISM Do these changes suggest a diagnosis ? McCUNE ALBRIGHT SYNDROME : McCUNE ALBRIGHT SYNDROME What are the features of the classic triad ? THE McCUNE ALBRIGHT SYNDROME: THE McCUNE ALBRIGHT SYNDROME POLYOSTOTIC FIBROUS DYSPLASIA CUTANEOUS HYPERPIGMENTATION ENDOCRINE HYPERFUNCTION The Classic TRIAD ... THE McCUNE ALBRIGHT SYNDROME: THE McCUNE ALBRIGHT SYNDROME POLYOSTOTIC FIBROUS DYSPLASIA Cancellous bone is replaced with immature woven bone and fibrous tissue Occurs in multiple sites ... especially long bones, ribs and skull Assymetry of the lesions is a typical feature Complications of Polyostotic Fibrous Dysplasia: Complications of Polyostotic Fibrous Dysplasia 1. pathological fractures … especially long bones 2. bony deformities 3. nerve compression … Typically, sclerosis at the base of skull in the region of the cavernous sinus causes optic and auditory nerve compression with hearing or visual loss. THE McCUNE ALBRIGHT SYNDROME: CUTANEOUS HYPERPIGMENTATION Large melanotic macules Assymetrical … often stop at the midline Irregular margins … THE McCUNE ALBRIGHT SYNDROME How do these lesions differ from the café au lait macules of Neurofibromatosis ? ”Coast of Maine” lesions, in contradistinction to the smooth “Coast of California”margins typical of the café au lait lesions of Neurofibromatosis: ”Coast of Maine” lesions, in contradistinction to the smooth “Coast of California”margins typical of the café au lait lesions of Neurofibromatosis California Maine THE McCUNE ALBRIGHT SYNDROME THE McCUNE ALBRIGHT SYNDROME: ENDOCRINE HYPERFUNCTION typically precocious puberty More commonly seen in girls Often dissonant (eg. Menarche or Thelarche in the absence of Adrenarche) but may appear consonant (resembling normal puberty) also … Hyperthyroidism Cushing’s syndrome Gigantism or Acromegaly THE McCUNE ALBRIGHT SYNDROME THE McCUNE ALBRIGHT SYNDROME: Sporadic Inheritance Sex: male = female Age: variable from 4 months into adulthood Other Features that have been described: Hypophosphataemic rickets Sudden death from cardiac arrhythmias Prolonged conjugated neonatal jaundice Mild hepatitis THE McCUNE ALBRIGHT SYNDROME Other notable features ... So what’s with this G-protein business?: So what’s with this G-protein business? A central figure in our story is FULLER ALBRIGHT Harvard endocrinologist his name has been linked to many syndromes … among them... McCune Albright Syndrome Albright’s Hereditary Osteodystrophy Despite quite different phenotypes, they have both been shown to be the result of G-protein abnormalities. THE PLAYERS: THE PLAYERS THE PLAYERS: The first description in the literature was of a 9 year old girl with precocious puberty, fragile bones and dermal pigmentation, described by Weill in Berlin in 1922. Fourteen years later in New York, a paediatrician named Donovan McCune described another 9 year old girl with precocious puberty, excessive skin pigmentation and hyperthyroidism. The following year, Albright became the first to delineate the Syndrome when he published a series of five cases in the NEJM. THE PLAYERS Slide24: THE PLAYERS THE PLAYERS: Di George summed up the state of play with the Syndrome in the Journal of Paediatrics in 1975. Most investigators, including Albright himself, had argued that the Syndrome was the result of hypersecretion of hypothalamic hormones. Di George cited several contemporaneous studies that provided evidence for autonomous endocrine hyperfunction, specifically …. Hyperthyroidism with suppressed TSH Precocious puberty with suppressed FSH, LH THE PLAYERS THE PLAYERS: THE PLAYERS The Lines of Blaschko : The Lines of Blaschko Another piece of the puzzle received attention in 1986 when a German dermatologist, Happle, noted that the areas of pigmentation follow the lines of Blaschko. These lines are a marker of the normal development of human skin, representing proliferation and migration of skin cells during embryogenesis. As you can see they are aligned along the axes of the limbs, and circumferentially around the trunk. Visible Lines = Mosaicism: They only become visible in individuals with conditions that affect the skin who bear some form of mosaicism. Essentially they are visible evidence for the clonal proliferation of two functionally different populations of cells. One of these clones contains a different amount of pigmentation to the other giving shape to these otherwise unseen lines. Visible Lines = Mosaicism THE PLAYERS: THE PLAYERS But, it was Gilman and Rodbell who opened the door to a solution to the puzzle. They were joint recipients of the Nobel Prize in 1994 for the discovery of the G-protein. THE G-PROTEIN is a TRANSDUCER: THE G-PROTEIN is a TRANSDUCER A mutated lymphoma cell was shown to have an Intact Receptor an Intact Adenyl Cyclase BUT NO cAMP production They studied Lymphoma cells with intact cAMP producing pathways Slide31: So how do they work at Molecular level ? THE G-PROTEIN is a TRANSDUCER: THE G-PROTEIN is a TRANSDUCER The G protein consists of three subunits … alpha, beta and gamma. When the related receptor is activated, the active subunit, alpha, binds GTP and separates from beta and gamma. It then exerts a stimulatory or inhibitory effect on the relevant target protein. This effect is terminated by the hydrolysis of GTP to GDP by the alpha subunit’s intrinsic GTPase activity, and the subunits recombine as inactive G protein. Take another look THE G-PROTEIN FAMILY: THE G-PROTEIN FAMILY G-Protein subunits include …  The Stimulatory G protein or Gs increases cAMP production mediating the effects of *Adrenergics *PTH * T4 *LH *ACTH *FSH *LH *MSH  The Inhibitory G protein or Gi decreases cAMP mediating the effects of *Adrenergic amines and many neurotransmitters  Others which act cGMP levels There is a family of alpha G protein subunits which mediate hormonal action by exerting stimulatory or inhibitory effects on Adenyl or Guanyl cyclase THE G-PROTEIN ABNORMALITY IN THE McCUNE ALBRIGHT SYNDROME: THE G-PROTEIN ABNORMALITY IN THE McCUNE ALBRIGHT SYNDROME DNA studies have demonstrated abnormalities in the GNAS1 gene on chromosome 20, which codes for Gs ADENYL CYCLASE cAMP THE G-PROTEIN ABNORMALITY IN THE McCUNE ALBRIGHT SYNDROME: THE G-PROTEIN ABNORMALITY IN THE McCUNE ALBRIGHT SYNDROME The mutation is at the site which codes for the intrinsic GTPase activity, responsible for mediating the inactivation of the alpha subunit. THE RESULT: constitutive activation of cAMP driven pathways in the absence of hormone stimulation. THE G-PROTEIN ABNORMALITY IN ALBRIGHT’S HEREDITARY OSTEODYSTROPHY: THE G-PROTEIN ABNORMALITY IN ALBRIGHT’S HEREDITARY OSTEODYSTROPHY THE DEFECT: AD absence of the maternal copy of Gs thus PTH fails to stimulate PTH receptor complex Another eponymous syndrome, Albright’s Hereditary Osteodystrophy is also known as Pseudohypoparathyroidism Type Ia Phenotypically: short stature & short digits Biochemically: PTH resistance [Hypocalcaemia with PTH] This mimics Gilman and Rodbell’s mutated Lymphoma cell So much for the molecular biology. What about the genetics of the McCune Albright Syndrome? : So much for the molecular biology. What about the genetics of the McCune Albright Syndrome? Family studies have shown the inheritance to be sporadic This is because there is a post- zygotic mutation THE GENETICS OF McCUNE ALBRIGHT SYNDROME: The timing during embryogenesis determines the severity of each case Early on: widespread tissue involvement Later: mild cases … there may only be a single adenoma THE GENETICS OF McCUNE ALBRIGHT SYNDROME The Mosaic Hypothesis is confirmed SO THAT’S McCUNE ALBRIGHT SYNDROMEWHAT ABOUT THIS LITTLE GUY ?: SO THAT’S McCUNE ALBRIGHT SYNDROME WHAT ABOUT THIS LITTLE GUY ? SO THAT’S McCUNE ALBRIGHT SYNDROMEWHAT ABOUT THIS LITTLE GUY ?: For the Fibrous Dysplasia: Careful monitoring of vision and hearing He may need a neurosurgical referral Pathological fractures are difficult Bisphosphonates may help with pain For the Hyperthyroidism: Antithyroid drugs [he has been started on Neomercazole] Radioactive iodine or Surgery SO THAT’S McCUNE ALBRIGHT SYNDROME WHAT ABOUT THIS LITTLE GUY ? What if he develops Precocious Puberty ?: What if he develops Precocious Puberty ? Testolactone, the aromatase inhibitor, is of proven efficacy Ketoconazole or Spironolactone are other inhibitors of testosterone synthesis that may be tried. FURTHER READING: FURTHER READING Farfel Z, Bourne HR, Iiri T. The expanding spectrum of G protein diseases. NEJM 1999; 340 (13): 1012–1020. OMIM Entry # 174800. The McCune Albright syndrome. www.ncbi.nlm.nih.gov/omim. Boston BA. McCune Albright syndrome. eMedicine Journal 2000; 3 (2). www.emedicine.com/ped/topic1386.htm. Weill A. Pubertas praecox und knochenbrüchigkeit. Klinische Wochenschrift 1922; 1: 2114-2115. McCune DJ. Osteitis fibrosa cystica. Am J Dis Child 1936; 52: 743-747. Albright F, Butler AM, Hampton AO, Smith PH. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. NEJM 1937; 216: 727-746. FURTHER READING (Cont.): FURTHER READING (Cont.) DiGeorge AM. Albright syndrome: Is it coming of age? J Paeds 1975; 87 (6): 1018-1020. Happle R. Lyonization and the lines of Blaschko. Human Genetics 1985; 70: 200-206. Happle R. The McCune Albright syndrome: a lethal gene surviving by mosaicism. Clinical Genetics 1986; 29: 321-324. Nobel eMuseum. Nobel prize in physiology or medicine 1994. www.nobel.se/medicine/educational/poster/1994/index.html. Zacharin M, O’Sullivan M. Intravenous pamodrinate treatment of polyostotic fibrous dysplasia associated with the McCune Albright syndrome. J Paeds 2000; 137 (3): 403-409.